R-(R*,S*)!-.beta.-methyl-.alpha.-phenyl-1-pyrrolidineethanol, commonly referred to as (1R,2S)-N-pyrrolidinyl norephedrine, is an important chiral mediator for an enantioselective addition reaction, which is a key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one, also known as DMP-266. As this chiral mediator is not commericially available, an efficient method for its preparation had to be developed.
The synthesis of DMP-266 and structurally similar reverse transcriptase inhibitors are disclosed in U.S. Pat. No. 5,519,021 and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enatioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 937-940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
The use of chiral mediators has been disclosed in the published literature as useful in enatioselective synthesis, in inducing the enantioselectivity of additions to aldhydes, enantioselectivity of deprotonation of meso-epoxides and enantioselectivity of proton abstraction, etc. (See P. J. Cox and N. S. Simpkins, Tetrahedron: Asymmetry 1991, 2(1), 1-26; M., Asami, et al., Tetrahedron: Asymmetry 1994, 5(5), 793-6; M. Ye, et al., Tetrahedron, 1994, 50(20), 6109-16; and M. Amadji, et al. J. Am. Chem. Soc. 1996, 118, 12483-4. )
The instant invention discloses an efficient method for the quantitative preparation and isolation of the enantiomers of the compound of formula I ##STR2##